Collaborative Research: Ideas Lab: The Role of Extracellular RNA in Intercellular and Interkingdom Communication

合作研究：创意实验室：细胞外 RNA 在细胞间和王国间通讯中的作用

• 批准号: 2243534
• 负责人: Patricia Baldrich
• 金额: $ 102.26万
• 依托单位: Donald Danforth Plant Science Center
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2243534&HistoricalAwards=false
• 关键词: Collaborative; Research; Ideas; Lab; Role

This project is a collaboration among seven laboratories with diverse and complementary expertise. The overarching goal of the project is to understand the role of extracellular RNA (exRNA) in communication between cells and in shaping the community of microbes, especially bacteria, that live on and inside plants, insects, and humans. These collections of microbes are often referred to as microbiomes and are critical for the health of plants and animals, including humans. A healthy microbiome promotes a healthy immune system, but how healthy microbiomes are maintained is poorly understood. This project will test the hypothesis that RNA secreted by host cells plays a central role in maintaining health both through communication among cells and by modifying the microbiome. RNA is best known for its key role in protein production inside cells, such as in RNA-based COVID vaccines. However, not all RNA encodes proteins, and cells produce more non-coding RNA than coding RNA, some of which is actively pushed into the environment by cells. This secreted RNA appears to be taken up by other cells, including bacteria and fungi, where it could potentially impact their growth. Understanding how exRNAs shape communication between cells and organisms will enable manipulation of exRNA communication in both agriculture and medicine, which will lead to development of environmentally friendly pesticides, as well as treatments that promote formation of healthy microbiomes in both plants and animals. This knowledge will also enable development of diagnostic and therapeutic tools for early detection and/or treatment of disease.All cellular organisms secrete RNAs. The functions of these extracellular RNAs (exRNAs), however, are poorly understood. Two likely functions are intercellular and interkingdom communication. Open questions abound in exRNA biology: how are exRNAs selected for secretion, how are they targeted to recipient cells, and what are their roles in normal health and organismal fitness? Arabidopsis leaf exRNA isolates are highly enriched in the post-transcriptional modification N6-methyladenosine (m6A) (as compared to total cellular RNA) suggesting that post-transcriptional modifications may tag specific RNAs for export. Consistent with this, human exosomal microRNAs are enriched with m6A (relative to cytosolic microRNAs). Interestingly, a large number of mammalian small non-coding RNAs (ncRNAs) that localize to the external cell surface were recently found to harbor specific sialylated glycan modifications. These observations suggest that specific RNA modifications tag RNAs for cellular export and direct entry into appropriate recipient cells. This project will 1) test the hypothesis that exRNAs have specific features marking them for secretion and uptake, both within and among species, 2) determine how exRNAs are transferred from signaler to receiver cells, and 3) assess the impact of exRNA on microbiome health and composition through examining human gut, insect gut, and leaf surface models.This project was co-funded by the Directorate for Biological Sciences, and the Plant Genome Research Program and the Plant Biotic Interactions Program in the Division of Integrative Organismal Systems.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目是七个具有多样和互补专业知识的实验室之间的合作。该项目的总体目标是了解细胞外RNA（EXRNA）在细胞之间的通信以及塑造生物在植物，昆虫和人类内部和内部的微生物社区中的作用。这些微生物的集合通常被称为微生物组，对于包括人类在内的动植物的健康至关重要。健康的微生物组促进了健康的免疫系统，但是对健康的微生物组的维持程度很低。该项目将检验以下假设：宿主细胞分泌的RNA在通过细胞之间的通信和修饰微生物组之间的交流和修饰的健康方面起着核心作用。 RNA以其在细胞内部蛋白质产生中的关键作用而闻名，例如基于RNA的Covid疫苗。但是，并非所有RNA都编码蛋白质，并且细胞产生的非编码RNA比编码RNA更多，其中一些被细胞积极地推入环境。该分泌的RNA似乎被其他细胞（包括细菌和真菌）吸收，在那里它可能会影响其生长。了解ExrNA如何塑造细胞与生物之间的通信将如何能够在农业和医学中处理Exrna通信，这将导致环保农药的发展，以及促进植物和动物中健康微生物组形成的治疗方法。这些知识还将能够开发出诊断和治疗工具，用于早期检测和/或治疗疾病。所有细胞生物都会分泌RNA。但是，这些细胞外RNA（EXRNA）的功能知之甚少。两个可能的功能是细胞间和跨间路通信。 Exrna生物学中的开放性问题比比皆是：如何选择分泌的Exrnas，它们如何针对受体细胞，以及它们在正常健康和有机体适应性中的作用是什么？拟南芥叶片分离株高度富集在转录后修饰N6-甲基二苯胺（M6A）中（与总细胞RNA相比），这表明转录后修饰可能会标记特定的RNA用于导出。与此相一致，人外泌体microRNA富含M6A（相对于胞质microRNA）。有趣的是，最近发现，将大量哺乳动物的小型非编码RNA（NCRNA）定位在外部细胞表面，它们具有特定的siaiallated Glycan修饰。这些观察结果表明，特定的RNA修饰标记RNA用于细胞出口并直接进入适当的受体细胞。该项目将1）检验以下假说：埃克雷纳群具有特定特征，标记了它们在物种内部和物种之间的分泌和吸收。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子优点和更广泛的影响标准通过评估值得支持的。